Alzheimer disease (AD) is an age-related progressive neurodegenerative disease. As a result of increases in the size of the aged population worldwide, AD has become an important social, economical and medical burden, affecting ~27 million individuals worldwide and 4-5 million individuals in the U.S. alone. Because the molecular mechanism of AD is not yet understood, there is no cure for the disease so far. The long-term objective of this application is to understand the molecular mechanism of the neurodegeneration in AD and, based on this knowledge, to develop strategies to prevent and treat the disease. The specific goal of this international research collaboration FIRCA grant (R03) is to foster international research collaboration between the applicant's laboratory in the U.S. and the foreign collaborator's laboratory in China. Because abnormal phosphorylation (a modification of protein by phosphate) and accumulation of neurofilaments (the major cytoskeletal proteins of the neuron) in the brain may contribute to degeneration of neurons in AD, the specific focus of the proposed studies is on understanding the role of O-GlcNAcylation (a modification of protein by sugar) in the phosphorylation and function of neurofilaments, which are abnormal in the brains of individuals with AD. The Specific Aims of this project are to (1) study the functional impact of O-GlcNAcylation on filament assembly and on axonal transport of neurofilaments and (2) study the vulnerability of various brain regions to NF hyperphosphorylation induced by decreased O-GlcNAcylation in the brain. This project will not only elucidate the biological relevance of neurofilament O-GlcNAcylation and its functional roles, thus providing the fundamental understanding of the role of dysregulation of neurofilaments in neurodegeneration of AD, but also foster the ongoing international research collaboration between the U.S. and China. With ~6 million individuals with AD, China has a huge demand for adequate research on the disease. The foreign collaborator of this FIRCA application is Dr. Yanqiu Deng, an Associate Professor of Pathophysiology at Tianjin Medical University, Tianjin, China. The proposed studies will be carried out at both the applicant's and the foreign collaborator's laboratories. Studies proposed in this application will complement, extend and enhance the significance of the applicant's parent grant (NIH R01 AG027429, 03/01/06-02/28/11) that targets the mechanism of the involvement of O-GlcNAcylation of tau protein in the neurodegeneration of AD. PUBLIC HEALTH RELEVANCE: Alzheimer disease is an age-related progressive neurodegenerative disease and is characterized by impaired memory, thinking, and behavior, leading to dementia and death. The objective of this project is to enhance international research collaboration on studies targeting the molecular mechanism of neurodegeneration of Alzheimer disease and, on the basis of this knowledge, to develop strategies to prevent and treat the disease.